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Brault et al. J Transl Genet Genom. 2025;9:1-10 Journal of Translational
DOI: 10.20517/jtgg.2024.83
Genetics and Genomics

Review Open Access

What can ATP content tell us about Barth syndrome
muscle phenotypes?

1,#
Jeffrey J. Brault , Simon J. Conway 2,#
1
Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
2
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
#
Authors contributed equally.
Correspondence to: Dr. Jeffrey J. Brault, Department of Anatomy, Cell Biology & Physiology, Indiana University School of
Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA. E-mail: jebrault@iu.edu; Dr. Simon J. Conway, Herman B. Wells
Center for Pediatric Research, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202, USA. E-
mail: siconway@iu.edu
How to cite this article: Brault JJ, Conway SJ. What can ATP content tell us about Barth syndrome muscle phenotypes? J Transl
Genet Genom. 2025;9:1-10. https://dx.doi.org/10.20517/jtgg.2024.83

Received: 19 Oct 2024 First Decision: 16 Dec 2024 Revised: 23 Dec 2024 Accepted: 6 Jan 2025 Published: 15 Jan 2025
Academic Editors: Hilary Vernon, Sanjay Gupta Copy Editor: Fangling Lan Production Editor: Fangling Lan

Abstract
Adenosine triphosphate (ATP) is the energy currency within all living cells and is involved in many vital
biochemical reactions, including cell viability, metabolic status, cell death, intracellular signaling, DNA and RNA
synthesis, purinergic signaling, synaptic signaling, active transport, and muscle contraction. Consequently, altered
ATP production is frequently viewed as a contributor to both disease pathogenesis and subsequent progression of
organ failure. Barth syndrome (BTHS) is an X-linked mitochondrial disease characterized by fatigue, skeletal
muscle weakness, cardiomyopathy, neutropenia, and growth delay due to inherited TAFAZZIN enzyme mutations.
BTHS is widely hypothesized in the literature to be a model of defective mitochondrial ATP production leading to
energy deficits. Prior patient data have linked both impaired ATP production and reduced phosphocreatine to ATP
ratios (PCr/ATP) in BTHS children and adult hearts and muscles, suggesting a primary role for perturbed
energetics. Moreover, although only limited direct measurements of ATP content and ADP/ATP ratio (an indicator
of the energy available from ATP hydrolysis) have so far been carried out, analysis of divergent BTHS animal
models, cultured cell types, and diverse organs has failed to uncover a unifying understanding of the molecular
mechanisms linking TAFAZZIN deficiency to perturbed muscle energetics. This review mainly focuses on the
energetics of striated muscle in BTHS mitochondriopathy.

Keywords: Barth syndrome, TAFAZZIN, cardiolipin, striated muscle, mitochondria, adenosine triphosphate,
energetics

© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0
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